1. Field of the Invention
The present invention relates to novel pyrrolo[2,1-c][1,4]benzodiazepine compounds. This invention also relates to a process for the preparation of novel pyrrolo[2,1-c][1,4]benzodiazepine compounds. These novel pyrrolo[2,1-c][1,4]benzodiazepine compounds are useful as antitumor agents. More particularly, they relate to a process for the preparation of 7-methoxy-8-{n-[4-(2-oxo-2H-4-chromenyl)piperazino]alkyl}-oxy-(11aS)-1,2,3,11a-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one and 7-methoxy-8-{n-[4-(7-alkoxy-8-methyl-2-oxo-2H-4-chromenyl)piperazino]alkyl}-oxy-(11aS)-1,2,3,11a-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5-one with aliphatic chain length variations for these compounds. The structural formula of these novel pyrrolo[2,1-c][1,4]benzodiazepines is given below.
wherein R1 is H or an alkoxy group selected from methoxy, ethoxy and propoxy groups, R2 is H or CH3 and n is an integer varying from 3-5.
2. Description of the Related Art
Pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics are commonly known as anthramycin class of compounds. In the last few years, a growing interest has been shown in the development of new pyrrolo[2,1-c][1,4]benzodiazepines (PBDs). These antibiotics react covalently with DNA to form an N2-guanine adduct that lies within the minor groove of duplex DNA via an acid-labile aminal bond to the electrophilic imine at the N10-C11 position (Kunimoto, S.; Masuda, T.; Kanbayashi, N.; Hamada, M.; Naganawa, H.; Miyamoto, M.; Takeuchi, T.; Unezawa, H. J. Antibiot., 1980, 33, 665.; Kohn, K. W. and Speous, C. L. J. Mol. Biol., 1970, 51, 551.; Hurley, L. H.; Gairpla, C. and Zmijewski, M. Biochem. Biophys. Acta., 1977, 475, 521.; Kaplan, D. J. and Hurley, L. H. Biochemistry, 1981, 20, 7572). The molecules have a right-handed twist, which allows them to follow the curvature of the minor groove of B-form double-stranded DNA spanning three base pairs. A recent development has been the linking of two PBD units through their C-8 positions to give bisfunctional-alkylating agents capable of cross-linking DNA (Thurston, D. E.; Bose, D. S.; Thomson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S. and Hurley, L. H. J. Org. Chem. 1996, 61, 8141).

Recently, PBD dimers have been developed that comprise two C2-exo-methylene substituted DC-81 subunits tethered through their C-8 position via an inert propanedioxy linker (Gregson, S. J.; Howard, P. W.; Hartely, J. A.; Brooks, N. A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R. and Thurston, D. E. J. Med. Chem. 2001, 44, 737). Recently, a noncross-linking mixed imine-amide PBD dimers have been synthesized that have significant DNA binding ability and potent antitumor activity (Kamal, A.; Ramesh, G. Laxman, N.; Ramulu, P.; Srinivas, O.; Neelima, K.; Kondapi, A. K.; Srinu, V. B.; Nagarajaram, H. M. J. Med. Chem. 2002, 45, 4679).
Naturally occurring pyrrolo[2,1-c][1,4]benzodiazepines belong to a group of antitumor antibiotics derived from Streptomyces species. Recently, there is much impetus for the PBD systems as they can recognize and bind to specific sequence of DNA. Examples of naturally occurring PBD's include anthramycin, DC-81, tomaymycin, sibiromycin and neothramycin.
However, the clinical efficacy for these antibiotics is hindered by several limitations, such as poor water solubility, cardiotoxicity, development of drug resistance and metabolic inactivation.